Factor XIII (FXIII) is the final enzyme in the blood coagulation cascade. In blood, FXIII is present in two forms. Plasma FXIII is produced in the liver and exists as a heterotetramer with two catalytic .alpha.-subunits and two noncatalytic .beta.-subunits (.alpha.2.beta.2) (Schwartz M. L., Pizzo S. V., Hill R. L., McKee P. A.: Human factor XIII from plasma and platelets: Molecular weights, subunit structure, proteolytic activation and crosslinking of fibrinogen and fibrin. J. Biol. Chem. 248:1395, 1973). Platelet FXIII is made up of only two .alpha.-subunits (.alpha.2). .alpha.2 is also found intracellularly in megakaryocytes, monocytoid cells, and cells of the placenta (Schwartz et al., supra; Henriksson P., Becker S., Lynch G., McDonagh J.: Identification of intracellular factor XIII in human monocytes and macrophages. J. Clin. Invest. 76: 528, 1985). When activated, FXIII plays a critical role in thrombosis by cross-linking .alpha..sub.2 -antiplasmin to fibrin and fibrin chains to one another.
Two types of enzymatic processes contribute to the formation of a blood clot. The first process involves zymogen and cellular activation and is mediated by thrombin and other serine proteases of the coagulation system. The second process involves the intermolecular cross-linking of fibrin and other proteins and is catalyzed by the transglutaminase, FXIII. These two processes converge in the clotting of fibrinogen.
Fibrinogen is cleaved by thrombin, resulting in the conversion of fibrinogen to the insoluble protein, fibrin, and the concomitant release of "activation peptides". Thrombin also cleaves an activation peptide from the .alpha.-subunit of FXIII, .alpha.2, to yield thrombin-cleaved .alpha.-subunit of FXIII (.alpha.2'), which then undergoes a conformational change to form the activated enzyme, .alpha.-subunit of FXIII (.alpha.2*) (Lorand L.: Activation of blood coagulation factor XIII. Ann. N.Y. Acad. Sci. 485:144, 1986). The .alpha.2* enzyme catalyzes the intermolecular formation of .epsilon.-(.gamma.-glutamyl)lysine cross-links between adjacent fibrin gamma chains and between contiguous fibrin alpha chains (Chen R, Doolittle RT: Isolation, characterization and location of a donor-acceptor unit from cross-linked fibrin. Proc. Natl. Acad. Sci. U.S.A. 66:472, 1970; Pisano J. J., Bronzert T. J., Peyton M. P., Finlayson J. S.: .epsilon.-(.gamma.-Glutamyl) lysine cross-links: determination in fibrin from normal and factor XIII-deficient individuals. Ann. N.Y. Acad. Sci. 202:98, 1972). Enzyme .alpha.2* also cross-links other plasma proteins, such as .alpha..sub.2 -antiplasmin (Tamaki T., Aoki N.: Cross-linking of -plasmin inhibitor and fibronectin to fibrin by fibrin-stabilizing factor. Biochim. Biophys. Acta 661:280, 1981) and fibronectin (Mosher D. F.: Cross-linking of cold-insoluble globulin by fibrin-stabilizing factor. J. Biol. Chem. 250:6614, 1975) to fibrin. The resulting fibrin mesh is resistant to mechanical or proteolytic disruption (Lorand L., Jacobsen A.: Accelerated lysis of blood clots. Nature 195:911, 1962).